Our laboratory has used yeast to model the cellular defects caused by the human proteins implicated in neurodegenerative diseases. We propose a high- throughput chemical screen using a yeast strain expressing human A2, a protein linked to Alzheimer's disease. Data from a pilot screen demonstrate that our yeast A2 assay is robust and reproducible. The proposed screen will enable us to probe a larger library at multiple concentrations and cover a broader chemical space. Hit compounds from this screen will be counter-screened against yeast models of other neurodegenerative diseases to determine selectivity, and will be further screened for toxicity in mammalian cells and efficacy in mammalian neurons. The ideal chemical candidates would have activity in both our primary yeast and secondary neuronal toxicity assays and would have a pharmacokinetic profile suitable for studies in transgenic mouse models of AD. These chemical probes will provide a complementary approach to deciphering the tangled mechanisms of toxicity and protection that we have begun to uncover through our genetic screens. PUBLIC HEALTH RELEVANCE: A2 peptide accumulates in the brains of patients with Alzheimer disease and may cause neurodegeneration, but its mechanism of action is not known. We propose to identify compounds that can alleviate the cellular toxicity of A2 and validate these in neuronal models. These probes will be valuable tools for dissecting A2 pathology and could potentially become the focus for future pre- clinical development.